High-dose enzyme replacement therapy in murine Hurler syndrome
High-dose enzyme replacement therapy in murine Hurler syndrome
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DOI：
10.1016/j.ymgme.2013.09.008
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发表时间：
2014-02-01
影响因子：
3.8
通讯作者：
Whitley, Chester B.
中科院分区：
文献类型：
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作者：
Ou, Li;Herzog, Tyler;Whitley, Chester B.
I 型粘多糖贮积症 (MPS I) 是一种全身性常染色体隐性遗传疾病，包括进行性神经变性、智力低下和 10 岁之前死亡。 MPS I 是由于溶酶体中 α-L-艾杜糖醛酸酶 (IDUA) 的缺乏以及随后糖胺聚糖 (GAG) 的积累造成的。静脉注射拉罗尼酶的临床酶替代疗法 (ERT) 可逆转 MPS I 疾病的某些方面（例如肝肿大、脾肿大、糖胺聚糖尿）并改善其他方面（例如肺功能、心脏病、关节病、运动耐量）。然而，由于血脑屏障（BBB）阻止酶到达中枢神经系统（CNS），因此对神经系统的益处被认为可以忽略不计。我们考虑了一种可能性，即非常高剂量的静脉注射拉罗尼酶可能能够少量穿过血脑屏障，并在大脑中提供一些代谢校正。为了解决这个问题，对成年 MPS I 小鼠施用高剂量拉罗尼酶（11.6 mg/kg，每周一次，4 周）。治疗小鼠皮质中的 IDUA 酶活性增加至野生型小鼠的 97% (p < 0.01)。与未经治疗的 MPS I 小鼠相比，皮质中的 GAG 水平降低了 63% (p < 0.05)。此外，免疫组织化学分析表明，治疗减少了 MPS I 小鼠继发性 GM3-神经节苷脂的积累。水 T 迷宫测试表明 MPS I 小鼠的学习异常有所减少 (p < 0.0001)。总之，重复、高剂量 ERT 促进了拉罗尼酶穿过 BBB，减少了 CNS 内的 GAG 积累，并挽救了认知障碍。 (C) 2013 Elsevier Inc. 保留所有权利。
Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease that is systemic, including progressive neurodegeneration, mental retardation and death before the age of 10 years. MPS I results from deficiency of alpha-L-iduronidase (IDUA) in lysosomes and subsequent accumulation of glycosaminoglycans (GAG). Clinical enzyme replacement therapy (ERT) with intravenous laronidase reverses some aspects of MPS I disease (e.g., hepatomegaly, splenomegaly, glycosaminoglycanuria) and ameliorates others (e.g., pulmonary function, cardiac disease, arthropathy, exercise tolerance). However, neurologic benefits are thought to be negligible because the blood-brain barrier (BBB) blocks enzyme from reaching the central nervous system (CNS). We considered the possibility that a very high dose of intravenous laronidase might be able to traverse the BBB in small quantities, and provide some metabolic correction in the brain. To address this question, high-dose laronidase was administered (11.6 mg/kg, once per week, 4 weeks) to adult MPS I mice. IDUA enzyme activity in the cortex of treated mice increased to 97% of that in wild type mice (p < 0.01). GAG levels in cortex were reduced by 63% of that from untreated MPS I mice (p < 0.05). Further, immunohistochemical analysis showed that treatment reduced secondary GM3-ganglioside accumulation in treated MPS I mice. Water T-maze tests showed that the learning abnormality in MPS I mice was reduced (p < 0.0001). In summary, repeated, high-dose ERT facilitated laronidase transit across the BBB, reduced GAG accumulation within the CNS, and rescued cognitive impairment. (C) 2013 Elsevier Inc. All rights reserved.